Pathogenesis of Alzheimer's disease (AD) is associated with accumulation of a hydrophobic β-amyloid (Aβ) peptide in the brain, which readily self-assembles into toxic oligomers and insoluble fibrils. Aβ oligomers are particularly destructive to excitatory synapses in the hippocampus as they bind to N-methyl-D-aspartic acid (NMDA) receptor proteins and cause their down regulation along with causing profound disturbances in synaptic morphology. In turn, Aβ fibrils form Aβ plaques, which are associated with deleterious activation of microglia and dystrophy of neurites passing along their vicinity. Long-term buildup of Aβ in the brain results in neurodegenerative cascade leading to widespread synaptic degeneration, formation of neurofibrillary tangles rand neuronal death resulting in occurrence of dementia in AD patients. Therefore, strategies modulating production, clearance and self-aggregation of Aβ are actively being pursued as disease modifying therapies.
Various agents can be used to treat medical conditions associated with AD.
However, despite the broad range of biological activities, the use of these agents has been limited by their toxicity at higher dose and lack of sufficient therapeutic efficacy at lower dose.
Thus, there remains a need to make new compounds which can have therapeutic efficacy for various neurodegenerative diseases including AD. The compounds, compositions, and methods described herein are directed toward this end.